Slow healing or lack of healing of dermal wounds (e.g., decubitus ulcers, severe burns and diabetic ulcers) and eye lesions (e.g., dry eye and corneal ulcers), is a serious medical problem, affecting millions of individuals and causing severe pain or death in many patients. Healing of surgical wounds can also be slow or otherwise problematic, particularly in aging and diabetic individuals. Although wounds may be quite dissimilar in terms of cause, morphology and tissue affected, they share a common healing mechanism. Each repair process ultimately requires that the correct type of cell migrate into the wound in sufficient numbers to have an effect: macrophages to debride wounds, fibroblasts for the formation of new collagen and other extracellular matrix (ECM) components in wounds where the extracellular matrix was damaged, capillary endothelial cells to provide the blood supply, and epithelial cells to ultimately cover the wounds.
However, under certain circumstances, such as burn wounds, and hereto lacking of sufficient living skin to support the regeneration of the wound, and then the wounds will last longer and have chances to develop severe infection that some time causes the loss of the lives. Hence resulted hypertrophic burn scars are notoriously difficult to treat because of their extensive tissue involvement.
The standard method for grafting extensive or deep burn wounds used full-thickness sheet grafts or narrowly meshed, thick, split-thickness skin grafts [Lattari,et al. J Burn Care Rehabil 18:147-155 (1997)]. This method, however, creates an additional complication-prone wound at the donor site. Donor sites can be painful and may develop infection, hypertrophic scarring, blistering, and hyper- or hypopigmentation. The problem of donor site scar hapertrophy occurs most frequently when a graft is taken at more than 0.012 inch thick, leaving a residual dermal bed that is too thin. Meanwhile, early and permanent coverage of extensive burn wounds is still difficult because of the shortage of the donor sites.
The unwounded dermis owes much of its structure and strength to the interactions of cells with the ECM. It is well understood now that migration of fibroblasts and keratinocytes plays an important role in wound healing. The ECM is the key dynamic assemblage of interacting molecules that regulate cell functions and interactions in response to stimulation of wounds. This matrix includes several proteins known to support the attachment of a wide variety of cells, including fibronectin, vitronectin, thrombospondin, collagens, and laminin. Although fibronectin is found at relatively low concentrations in unwounded skin, plasma fibronectin deposition occurs soon after wounding. When tissue is damaged, the ECM must be replaced to provide a scaffold to support cell attachment and migration. In addition to providing a scaffold, extracellular matrices can also direct cellular proliferation and differentiation. An extracellular matrix can, therefore, direct healing of a tissue in such a way that the correct tissue geometry is restored.
Acceleration of the healing process can be greatly aided by a better understanding of the factors that influence the synthesis of granulation tissue, which fills the wound before epithelialization. An important phase of early wound healing involves fibroblast secretion of glycosaminoglycans (GAGs), which form a hydrophilic matrix suitable for remodeling during healing. Tissue-engineering techniques generally focus on mimicking the ECM by creating a scaffolding of resorbable materials that serves to promote wound healing. However, the use of GAGs in such materials is hindered by the instability of free GAGs.
Modification of GAGs, such as hyaluronan, in order to provide more stable structures has been an area of interest in this field. For example, U.S. Pat. No. 4,851,521 describes esters of hyaluronic acid in which all or only a portion of the carboxylic groups of the acid are esterified. See also Kuo J W et al., Bioconjugate Chem 2:232-241(1991). These GAG modifications however, alter the biological activity of the GAGs and renders them less effective than their free counterparts. In addition, structures formed with these esterified GAGs are instable when in contact with liquid, such as body fluids, and thus structures composed of these molecules do not retain their integrity following application to a subject.
There is a need in the art for compositions, devices and methods for providing site-specific GAG administration, and in particular for GAG structures that are stable and cell or tissue accessible in vivo and which provide bioavailable GAG.